Re-evaluating currently available data and suggestions for planning randomised controlled studies regarding the use of hydroxyethyl starch in critically ill patients - a multidisciplinary statement

Meybohm et al. Critical Care 2013, 17:R166 http://ccforum.com/content/17/4/R166 RESEARCH Open Access Re-evaluating currently available data and suggestions for planning randomised controlled studies regarding the use of hydroxyethyl starch in critically ill patients - a multidisciplinary statement Patrick Meybohm1, Hugo Van Aken2, Andrea De Gasperi3, Stefan De Hert4, Giorgio Della Rocca5, Armand RJ Girbes6, Hans Gombotz7, Bertrand Guidet8, Walter Hasibeder9, Markus W Hollmann10, Can Ince11, Matthias Jacob12, Peter Kranke13, Sibylle Kozek-Langenecker14, Stephan Alexander Loer15, Claude Martin16, Martin Siegemund17, Christian Wunder13 and Kai Zacharowski1* Abstract Introduction: Hydroxyethyl starch (HES) is a commonly used colloid in critically ill patients. However, its safety has been questioned in recent studies and meta-analyses. Methods: We re-evaluated prospective randomised controlled trials (RCT) from four meta-analyses published in 2013 that compared the effect of HES with crystalloids in critically ill patients, focusing on the adherence to ‘presumably correct indication’. Regarding the definition of ‘presumably correct indication’, studies were checked for the following six criteria (maximum six points): short time interval from shock to randomisation (<6 h), restricted use for initial volume resuscitation, use of any consistent algorithm for haemodynamic stabilisation, reproducible indicators of hypovolaemia, maximum dose of HES, and exclusion of patients with pre-existing renal failure or renal replacement therapy. Results: Duration of fluid administration ranged from 90 min up to a maximum of 90 days. Four studies considered follow-up until 90-day mortality, three studies 28-/30-day mortality, whereas four studies reported only early mortality. Included studies showed a large heterogeneity of the indication score ranging between 1 and 4 points with a median (25%; 75% quartile) of 4 (2; 4). Conclusions: The most important question, whether or not HES may be harmful when it is limited to immediate haemodynamic stabilisation, cannot be answered yet in the absence of any study sufficiently addressing this question. In order to overcome the limitations of most of the previous studies, we now suggest an algorithm emphasising the strict indication of HES. Additionally, we give a list of suggestions that should be adequately considered in any prospective RCT in the field of acute volume resuscitation in critically ill patients. Introduction Several previous trials [1-3] question the safety of hydroxyethyl starch (HES) solutions compared to crystalloid solutions in critically ill patients, whereas other trials did not suggest any adverse effects [4-7]. These diverging * Correspondence: 1 Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany Full list of author information is available at the end of the article results may be the consequence of multiple factors including different patient populations and types of HES (particularly in terms of molecular weight, substitution coefficient, raw material, and concentration [8,9]). However, we believe that one of the most important factors has not yet been explored in detail. In contrast to current practice and to package inserts, colloids should primarily be supposed to replace intravascular volume loss and depletion and should be administered under strict conditions. © 2013 Meybohm et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Meybohm et al. Critical Care 2013, 17:R166 http://ccforum.com/content/17/4/R166 In previous trials [1-3], however, fluid therapy, including administration of HES, was often neither standardised nor limited regarding dose, time frame or selection of patients at risk. It is even more inscrutable as those studies recommending not using colloids in general on the intensive care unit (ICU) had stabilised their patients with colloids before randomisation [1-3]. One of the next fundamental problems in the field of fluid therapy in critically ill patients is the divergence and impreciseness of terms specifying fluid therapy at all during the last decades. In this respect, we choose to use the term ‘fluid administration’ for maintenance of fluid balance (a condition where crystalloids should be preferred) and the term ‘acute volume resuscitation’ for the treatment of acute volume depletion (a condition where colloids might be preferred). The European Medicines Agency’s (EMA’s) Pharmacovigilance Risk Assessment Committee (PRAC) concluded on 14 June 2013, that the available evidence suggests that the benefits of solutions containing HES no longer outweigh their risks and therefore recommended that the marketing authorisations for these medicines be suspended. Unfortunately, the PRAC has extrapolated these results to all patients irrespective of underlying conditions although there are still ongoing controversies on this subject due to unpublished data (CRYSTAL [10], BaSES [7], RAFTinG [11] and so on), and the use of HES in non-septic patients (for example intraoperative use) has not been addressed in the aforementioned studies, raising concerns about the safety of HES. In this review, we discuss recent prospective randomised controlled trials (RCTs) comparing HES with crystalloids for fluid therapy in critically ill patients focusing on the adherence to a ‘presumably correct indication’, and give suggestions for the design of future prospective RCTs. Material and methods In a first step, we screened the four recent meta-analyses published in 2013 [12-15] including RCTs with critically ill patients following sepsis, trauma, burns or any other disease hospitalised in an ICU. The intervention group received any type of HES. Control patients received 0.9% saline, Ringer’s acetate, or Ringer’s lactate. We excluded trials that exclusively compared HES with either other synthetic colloid or albumin that may potentially induce equally harmful effect and thereby mask any effects of HES. We prospectively decided to include only studies published in English. In a second step, we analysed studies on the adherence to ‘presumably correct indication’ using both the four meta-analyses [12-15] and original published manuscripts. Page 2 of 10 Then, we defined the following six criteria and generated a six-point score: 1. Did the authors randomise patients within a maximum of 6 h after the first sign of shock? This arbitrary time period was chosen based on Rivers et al. [16] and the Surviving Sepsis Campaign Guidelines [17]. 2. Did the authors restrict HES for initial volume resuscitation? (We acknowledge that this issue is in conflict with its licensing (...truncated)